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Volume 271, Number 46, Issue of November 15, 1996 pp. 29238-29244
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Topoisomerase II·Etoposide Interactions Direct the Formation of Drug-induced Enzyme-DNA Cleavage Complexes

(Received for publication, August 5, 1996)

D. Andrew Burden Dagger , Paul S. Kingma Dagger , Stacie J. Froelich-Ammon Dagger , Mary-Ann Bjornsti par , Marcia W. Patchan ** , Richard B. Thompson ** and Neil Osheroff Dagger Dagger Dagger

From the Departments of Dagger  Biochemistry and Dagger Dagger  Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, the par  Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and the ** Department of Biological Chemistry, University of Maryland School of Medicine, Baltimore, Maryland 21201-1503

Topoisomerase II is the target for several highly active anticancer drugs that induce cell death by enhancing enzyme-mediated DNA scission. Although these agents dramatically increase levels of nucleic acid cleavage in a site-specific fashion, little is understood regarding the mechanism by which they alter the DNA site selectivity of topoisomerase II. Therefore, a series of kinetic and binding experiments were carried out to determine the mechanistic basis by which the anticancer drug, etoposide, enhances cleavage complex formation at 22 specific nucleic acid sequences. In general, maximal levels of DNA scission (i.e. Cmax) varied over a considerably larger range than did the apparent affinity of etoposide (i.e. Km) for these sites, and there was no correlation between these two kinetic parameters. Furthermore, enzyme·drug binding and order of addition experiments indicated that etoposide and topoisomerase II form a kinetically competent complex in the absence of DNA. These findings suggest that etoposide· topoisomerase II (rather than etoposide·DNA) interactions mediate cleavage complex formation. Finally, rates of religation at specific sites correlated inversely with Cmax values, indicating that maximal levels of etoposide-induced scission reflect the ability of the drug to inhibit religation at specific sequences rather than the affinity of the drug for site-specific enzyme-DNA complexes.


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